Abstract
Rationale
Previously, we reported that the GABAA receptor containing α5 subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the α5 receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known.
Objective
In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (Kd~ 0.40 nM) and selectivity (~67.3-fold) for the α5 receptor, was investigated for its capacity to antagonize EtOH’s reinforcing, motor impairing, and sedative effects in Long-Evans rats.
Methods
Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOH’s motor-impairing effects in an oscillating bar task, while EtOH’s sedative effects were measured in the open field.
Results
RY024 (0.125−3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0−15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field.
Conclusion
The results suggest the GABAA receptor containing α5 subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.
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Acknowledgements
This research was supported in part by grants AA10406, AA11555, and AA12407 (H.L.J.) from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) and MH 46851 (J.M.C.) from the National Institute of Mental Health (NIH). Pete McKay was supported in part by a UROP stipend from the School of Science at IUPUI. Katrina Foster and Marin Garcia were supported in part by grant T35 M from the National Heart Lung and Blood Institute of the NIH (Short Term Training Program for Minority Students in Biomedical Research). Katrina Foster was also supported in part by a Minority Neuroscience Fellowship from the American Psychological Association and the Alcohol Research Center Training Grant from NIAAA (AA07462).
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McKay, P.F., Foster, K.L., Mason, D. et al. A high affinity ligand for GABAA-receptor containing α5 subunit antagonizes ethanol’s neurobehavioral effects in Long-Evans rats. Psychopharmacology 172, 455–462 (2004). https://doi.org/10.1007/s00213-003-1671-z
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DOI: https://doi.org/10.1007/s00213-003-1671-z